Infection of Human Retinal Pigment Epithelium with Chlamydia trachomatis

Boiko, Ernest V.; Maltsev, Dmitrii S.; Savicheva, Alevtina; Shalepo, Kira V.; Khusnutdinova, Tatyana A.; Pozniak, A L; Kvetnoĭ, I M; Polyakova, V. O.; Суетов, А. А.

doi:10.1371/journal.pone.0141754

Cited by 3 publications

(3 citation statements)

References 26 publications

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“…Telomerase-immortalised RPE1 cells are widely applied to study endocytic pathways [ 31 , 32 ], and are permissive to C . trachomatis infection [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

Chlamydia exploits filopodial capture and a macropinocytosis-like pathway for host cell entry

et al. 2018

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Pathogens hijack host endocytic pathways to force their own entry into eukaryotic target cells. Many bacteria either exploit receptor-mediated zippering or inject virulence proteins directly to trigger membrane reorganisation and cytoskeletal rearrangements. By contrast, extracellular C. trachomatis elementary bodies (EBs) apparently employ facets of both the zipper and trigger mechanisms and are only ~400 nm in diameter. Our cryo-electron tomography of C. trachomatis entry revealed an unexpectedly diverse array of host structures in association with invading EBs, suggesting internalisation may progress by multiple, potentially redundant routes or several sequential events within a single pathway. Here we performed quantitative analysis of actin organisation at chlamydial entry foci, highlighting filopodial capture and phagocytic cups as dominant and conserved morphological structures early during internalisation. We applied inhibitor-based screening and employed reporters to systematically assay and visualise the spatio-temporal contribution of diverse endocytic signalling mediators to C. trachomatis entry. In addition to the recognised roles of the Rac1 GTPase and its associated nucleation-promoting factor (NPF) WAVE, our data revealed an additional unrecognised pathway sharing key hallmarks of macropinocytosis: i) amiloride sensitivity, ii) fluid-phase uptake, iii) recruitment and activity of the NPF N-WASP, and iv) the localised generation of phosphoinositide-3-phosphate (PI3P) species. Given their central role in macropinocytosis and affinity for PI3P, we assessed the role of SNX-PX-BAR family proteins. Strikingly, SNX9 was specifically and transiently enriched at C. trachomatis entry foci. SNX9-/- cells exhibited a 20% defect in EB entry, which was enhanced to 60% when the cells were infected without sedimentation-induced EB adhesion, consistent with a defect in initial EB-host interaction. Correspondingly, filopodial capture of C. trachomatis EBs was specifically attenuated in SNX9-/- cells, implicating SNX9 as a central host mediator of filopodial capture early during chlamydial entry. Our findings identify an unanticipated complexity of signalling underpinning cell entry by this major human pathogen, and suggest intriguing parallels with viral entry mechanisms.

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“…Telomerase-immortalised RPE1 cells are widely applied to study endocytic pathways [ 31 , 32 ], and are permissive to C . trachomatis infection [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

Chlamydia exploits filopodial capture and a macropinocytosis-like pathway for host cell entry

et al. 2018

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“…The RPE is a target for numerous pathogens including viruses, such as Ebola [40], CMV [41,60], Varizella Zoster [61], and Influenza virus [62] or bacteria such as Chlamydia trachomatis [63]. In this context, the eye has been proposed to act as a reservoir, in particular for Ebola virus [18,40,64].…”

Section: Discussionmentioning

confidence: 99%

Zika virus induces strong inflammatory responses and impairs homeostasis and function of the human retinal pigment epithelium

et al. 2019

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BackgroundZika virus (ZIKV) has recently re-emerged as a pathogenic agent with epidemic capacities as was well illustrated in South America. Because of the extent of this health crisis, a number of more serious symptoms have become associated with ZIKV infection than what was initially described. In particular, neuronal and ocular disorders have been characterized, both in infants and in adults. Notably, the macula and the retina can be strongly affected by ZIKV, possibly by a direct effect of the virus. This is supported by the detection of replicative and infectious virus in lachrimal fluid in human patients and mouse models.MethodsHere, we used an innovative, state-of-the-art iPSC-derived human retinal pigment epithelium (RPE) model to study ZIKV retinal impairment.FindingsWe showed that the human RPE is highly susceptible to ZIKV infection and that a ZIKV African strain was more virulent and led to a more potent epithelium disruption and stronger anti-viral response than an Asian strain, suggesting lineage differences. Moreover, ZIKV infection led to impaired membrane dynamics involved in endocytosis, organelle biogenesis and potentially secretion, key mechanisms of RPE homeostasis and function.InterpretationTaken together, our results suggest that ZIKV has a highly efficient ocular tropism, which creates a strong inflammatory environment that could have acute or chronic adverse effects.FundThis work was funded by Retina France, REACTing and La Région Languedoc-Roussillon.

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“…21 The findings of these previous reports support the concept that mycoplasma directly stimulates leukocytes, thereby initiating the inflammatory responses by a mechanism that differs from the other bacteria. In contrast, RPE infected with chlamydia has been reported to be able to upregulate secretion of IL-8, 22 IL-6, and VEGF. 23 Thus, mycoplasma infection might also have influenced the cytokine production of RPE cells, thereby enhancing the ocular inflammation and neovascularization in our current study cases.…”

Section: Discussionmentioning

confidence: 92%

Mycoplasma Ocular Infection in Subretinal Graft Transplantation of iPS Cells-Derived Retinal Pigment Epithelial Cells

Makabe

Sugita

Hono

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To report occurrence of acute severe inflammation after surgical implantation of mycoplasma-infected induced pluripotent stem cell-derived RPE (iPS-RPE) cells into the eyes of healthy primates, and determine the immunopathological mechanisms of the inflammation. METHODS.Ophthalmic allogeneic transplantation of iPS-RPE cells was performed in the subretina of major histocompatibility complex (MHC)-matched (two eyes) and MHCmismatched (one eye) healthy cynomolgus monkeys. The clinical course after transplantation was observed using color fundus photography, fluorescence angiography, and optical coherence tomography. After the animals were killed at 1 month after surgery, eyeballs were removed and pathologically examined. Microorganisms were analyzed by PCR methods and BLAST analysis using preserved graft iPS-RPE cells and the recipients' vitreous humor. Mixed lymphocyte-RPE assay was performed on the mycoplasma-infected and noninfected iPS-RPE cells in vitro. RESULTS.In tested eyes, abnormal findings were observed in the grafted retina 2 weeks after surgery. Here, we observed retinal vasculitis and hemorrhage, retinal detachment, and infiltration of inflammatory cells into the retina of the eyes. One month after surgery, animals were killed due to the severe immune responses observed. Using PCR methods, sequence analysis detected mycoplasma-DNA (Mycoplasma arginini species) in both the grafted RPE cells and the collected vitreous fluids of the monkeys. Mixed lymphocyte-RPE assay revealed that the infected iPS-RPE cells enhanced the proliferation of inflammatory cells in vitro. CONCLUSIONS.Transplantation of graft iPS-RPE cells contaminated with mycoplasma into the subretina caused severe ocular inflammation. Mycoplasma possesses the ability to cause immune responses in the host.

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Infection of Human Retinal Pigment Epithelium with Chlamydia trachomatis

Cited by 3 publications

References 26 publications

Chlamydia exploits filopodial capture and a macropinocytosis-like pathway for host cell entry

Chlamydia exploits filopodial capture and a macropinocytosis-like pathway for host cell entry

Zika virus induces strong inflammatory responses and impairs homeostasis and function of the human retinal pigment epithelium

Mycoplasma Ocular Infection in Subretinal Graft Transplantation of iPS Cells-Derived Retinal Pigment Epithelial Cells

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